Tuesday, September 13, 2011

Fat Tissue Insulin Sensitivity and Obesity

In this post, I'll discuss a few more facts pertaining to the idea that elevated insulin promotes the accumulation of fat mass.

Insulin Action on Fat Cells Over the Course of Fat Gain

The idea that insulin acts on fat cells to promote obesity requires that insulin suppress fat release in people with more fat (or people who are gaining fat) to a greater extent than in lean people. As I have written before, this is not the case, and in fact the reverse is true. The fat tissue of obese people fails to normally suppress fatty acid release in response to an increase in insulin caused by a meal or an insulin injection, indicating that insulin's ability to suppress fat release is impaired in obesity (1, 2, 3). The reason for that is simple: the fat tissue of obese people is insulin resistant.

There has been some question around the blogosphere about when insulin resistance in fat tissue occurs. Is it only observed in obese people, or does it occur to a lesser extent in people who carry less excess fat mass and are perhaps on a trajectory of fat gain? To answer this question, let's turn the clocks back to 1968, a year before Neil Armstrong first set foot on the moon.

The question was first investigated by Dr. Jules Hirsch's group (4). They took fat biopsies from people with a range of different fat masses, exposed them to insulin, and determined the degree of insulin sensitivity of the biopsies. They found that insulin sensitivity of fat tissue declines as the size of fat cells increases. This was true across all cell sizes, not only the largest ones. As body fat gain mostly involves an increase in fat cell size rather than number, this suggests that fat tissue insulin sensitivity progressively declines as fat mass increases.

But they went further. They caused weight loss in their obese subjects using a calorie-restricted diet (15:45:40 protein:carb:fat), which shrunk their fat cell size. Following this intervention, insulin sensitivity in fat tissue increased, and both the blood glucose and insulin response to an oral glucose load improved considerably. They concluded:

These data are consistent with the rest of the literature suggesting that elevated insulin and insulin resistance are the result of obesity. They suggest that excess fat mass, particularly enlarged fat cells, is the ultimate cause of insulin resistance. This hypothesis has been buttressed further since 1968.

The Relationship Between Fasting Insulin and Future Weight Gain

As a further data point, consider the review paper published in 2007 by Hivert and colleagues (5). They reviewed all the studies that examined the relationship between fasting and/or post-meal insulin level and future weight gain (there are a number of them). Here's what they found:

The majority of prospective studies that included non-obese adults failed to show an association between insulin level at baseline and future weight gain.

On the other hand, other large cohort studies have shown that insulin resistance, which is usually associated with high plasma insulin levels, could be protective against weight gain.

High insulin does not generally predict future weight gain, and sometimes it even predicts lower future weight gain. This could be because of insulin's anti-obesity action in the brain, although that isn't clear because we don't know how hypothalamic insulin sensitivity tracks with hyperinsulinemia.

The Case of Diazoxide

Much fuss has been made about a study showing that the potassium channel activating drug diazoxide accelerates weight loss in obese people (6). One of the effects of this drug is a substantial reduction in insulin secretion, which is why it's used to treat hypoglycemia.

There are a number of problems with using this study to support the insulin hypothesis of obesity. One problem is that the finding has not always been replicated by other investigators (7). Also, this drug is already approved by the FDA for the treatment of hypoglycemia and hypertension. If it's so effective for fat loss, why isn't it being used as a fat loss drug?

A second problem appears as you sort through the first study's results. Basal metabolic rate and the proportion of carbohydrate and fat being used for fuel remained unchanged by diazoxide, suggesting that even if more fatty acids were being released by fat cells, they were not being burned at a faster rate, and thus they were also being re-incorporated into fat cells at an equally high rate. Think about this for a moment. Diazoxide decreased fasting insulin by 36 percent, and this had no effect whatsoever on fat burning or resting energy expenditure. This study confirms, ironically, that insulin does not regulate the net fatty acid flux of fat cells. Even if reducing insulin increases fat release from fat cells, if the fat is not burnt, it just does a loop through the circulation and ends up right back where it started. This is partially because insulin is not the main factor controlling fat re-incorporation into fat cells-- that job seems to be held by acylation-stimulating protein (ASP).

The fat loss coupled with unchanged basal metabolic rate means that either a) diazoxide made them start exercising alot, and/or b) they ate less. Since I've never heard of a drug that causes obese people to run three miles a day, it was almost certainly (b). So did reduced insulin action on their fat cells make them eat less? Given that fat cells don't regulate food intake (except indirectly via their production of leptin, which acts in the brain), and the brain does, perhaps we should shift our focus to the brain for a moment.

But first, what is diazoxide? It activates ATP-dependent potassium channels, which are required for glucose sensing by the insulin-secreting pancreatic beta cells. But as the biologists in the crowd may know, these channels appear in a lot of places in the body. One of the places they appear is in the smooth muscle tissue that lines the arteries, which may be why diazoxide is used to treat hypertension. Another place they appear is in the brain, where they regulate the electrical activity that is intrinsic to neuron function.

As the hypothalamus is a critical area regulating food intake, it makes sense to see if diazoxide can influence the activity of neurons there. It turns out, diazoxide influences the activity of POMC neurons, one of the critical cell types that regulates food intake in mammals (8). As these cells are contained in the hypothalamus, a region that has a high blood-brain-barrier permeability, it is plausible that diazoxide actually exerts its effect there. The larger point is that diazoxide is not a specific drug-- it has effects on many parts of the body, so one cannot assume that its effect on body weight in some studies is due to a reduction in circulating insulin. The evidence on diazoxide does not support the idea that it causes fat loss by reducing insulin action on fat cells. Other mechanisms are more plausible at this point.

Drugs that influence food intake and/or body fatness usually do so via an effect on the brain. For example, rosiglitazone is an anti-diabetic drug that increases insulin sensitivity. One side effect is fat gain. Originally, it was postulated that fat gain was due to the effects of rosiglitazone on fat cells. Recently, it was shown by Dr. Jerrold Olefsky, in collaboration with my colleagues at UW, that rosiglitazone exerts its obesity-promoting effect mostly via the brain (9). This same story has repeated itself many times in the scientific literature, therefore whenever an intervention causes a change in food intake or fat mass, the first thing I think is "what's happening in the brain?"

Conclusion

High circulating insulin is probably an adaptive response to insulin resistance in the body, which develops as fat cells enlarge and become less effective at trapping fatty acids and keeping them where they should be (there may also be a contribution from inflammation that may or may not be independent of the changes in fatty acid handling). Elevated insulin is probably the body's way of trying to compensate for this defect and keep fat in fat cells, but it does not fully compensate for the insulin resistance in fat tissue that progressively develops as fat cells enlarge. Evelyn Kocur has written about this quite a bit. This defect can be largely reversed by fat loss, as demonstrated by the fact that a number of fat loss diets, including low-carbohydrate, low-fat and calorie restriction diets lead to improved insulin action as long as sufficient fat is lost.

I have pointed out the reasons why the carbohydrate-insulin-fat hypothesis is not generally considered viable by the scientific community. I feel I have convinced those who are able to be convinced. I can't convince everyone, and that's all right. It's time for me to move on from this topic, and on to more useful things!

84 comments:

Thanks for this Stephan. Can you give us a list of the major dietary factors that cause fat cells to swell? I know high sodium is supposed to be one, and possibly magnesium deficiency, but I'm not aware of others. Probably dietary fat too then, since it's more prone to be stored as fat than carbs?

Aside from just eating less (tricky, as we know), taking out certain Neolithic fat cell-affecting elements would go a long way for quick gains in health.

This is really depressing. In all honesty the title should have read, "Dear Gary Taubes". I have noticed some fracturing of this community recently and it is saddening. We really should work through our differences since the subject of obesity is obviously larger than all of us, (no pun intended). I enjoy reading everyone's genuine efforts in this struggle. Oh, were there less bias in scientific research and corresponding dialogue.

One thing I cannot ignore is the fact that I severely restricted carbohydrates and lost 130 pounds over one year. No set point, no plateau, just consistent weight loss (without hunger) and maintenance of lean muscle mass until my BMI diminished from 40.3 to 23.3 (without exercise BTW). (This impacts my bias I am sure).

What do scientists say about that? It would be nice to learn the exact mechanisms but I am afraid it will continue to be murky. What I do know is I followed the information found in GCBC. Is it wrong? I am not sure and I crave a greater understanding. I have read many of your posts with great interest and newly gained insight. This one sounds like you are trying to convince yourself more than you are trying to convince your readers. Perhaps it is the close proximity of events.

There are multiple mechanisms to this quandary of fat accumulation. To disregard your or others' ideas without relevant and sincere integration into the larger picture of our collective obesity sequelae (which apparently has not been attempted yet) is a disservice to us all.

I am hopeful we can and will piece this all together and reverse obesity's current trending course.

“The idea that insulin acts on fat cells to promote obesity requires that insulin suppress fat release in people with more fat (or people who are gaining fat) to a greater extent than in lean people.”

I just don’t think this can be right.

Let me set up a naïve model to explain why. Think of the adipocyte as a leaky balloon. The more air (fat) the balloon contains, the greater the rate of leakage. Let’s attach a pump to the inlet of the balloon and call it insulin. The harder the pump (insulin) works, the greater the rate of inflation. At any particular work rate of the pump (insulin level), the balloon will settle at a dynamic equilibrium at which the rate of leakage equals the rate of inflation.

Here’s the good bit. As the balloon inflates, the air pressure within it increases. This means that the pump has to do more work, against the air pressure, to introduce additional quantities of air. The balloon (adopicyte) becomes increasingly resistant to the effect of the pump (insulin). Yet, the following is a true statement: the harder the pump works, the bigger the balloon.

I don’t pretend that this is some kind of analogy, but what it does demonstrate is the existence of a physical system with inflationary and deflationary mechanisms, which becomes increasingly resistant to the inflationary mechanism, but where the overall state of inflation is nevertheless determined by the activity of the inflationary mechanism in a monotonically increasing way.

Thus, the idea that insulin acts on fat cells to promote obesity does not require that insulin suppress fat release in people with more fat (or people who are gaining fat) to a greater extent than in lean people; it requires only that higher levels of insulin suppress fat release to a greater extent that lower levels, whether the person is obese or lean. The phenomenon of insulin resistance can only tell us the extent to which higher levels of insulin suppress fat release; it does not deny the existence of that suppressive effect. So, insulin resistance does not invalidate the insulin hypothesis.

If you accept that there is a dynamic equilibrium of sorts between the effect of insulin and the tendency of larger adopicytes to leak FFAs at a greater rate, then it follows that insulin levels and fat mass are going to track with each other. Observational studies aren’t going to be able to sort out the direction of causality, and you wouldn’t expect insulin levels to predict future weight gain (independently of current fat mass).

For anyone interested, CLA is supposed to decrease adipocyte size. I've also read two studies in Japan showing that "Kurozu" (traditionally fermented rice vinegar) does this too. Anyone with some more tricks in this department? Cheers.

I like the current state of discord. Why? because there is in fact not enough evidence to clarify the big picture. We have bits and pieces of the puzzle, a handfull of theoretical models, but no one with deep pockets is interested in footing the bill to end the murkiness - there just isn't a good business case for changing the status quo. I like to see Guyenet pitted against Taubes and Petro, because it keeps both sides honest. They act as each other's watch dogs (even when Taubes doesn't seem to be listening, I think he actually is ;) ).So keep at it, Stephan, we are in fact hearing you. I'm one of the people blessed by improved health and ideal weight after reading GCBC and jumping on the MDA bandwagon, but I also feel that the insulin resistance model is flimsy: insulin resistance looks like a perfectly functional negative feedback mechanism to me, and like you I haven't seen compelling evidence that it is just another innocent bystander like cholesterol. There must be more to it than just this.And although I don't subscribe the whole "palatability model" for obesity, I agree with you that the brain has to be looked at more thoroughly than it is today, in the issues of obesity and metabolic health.So cheers, keep up the effort, the fight is just beginning and we all stand to win.

(I'm the "Unknown" up there.... somehow the google login didn't go right.)Typo: I actually meant "insulin resistance looks like a perfectly functional negative feedback mechanism to me, and like you I haven't seen compelling evidence that it ISN'T just another innocent bystander like cholesterol."

How does the difference between physiological insulin resistance (i.e. the glucose-preserving adaptation to a ketogenic diet) and pathological insulin resistance play into this? Obviously insulin levels would be low int he former case, high in the latter. I think this is another concept that not everyone gets the distinction correctly, much like insulin spikes vs. hyperinsulinemia.

Remember that the insulin curve follows the glucose curve but is delayed in phase, so on which is the brain queuing off? Fat egress from fat cells occurs mainly when the insulin is lower, and blood FFA concentration is lower than the cell FFA concentration (diffusion), so there are at least two control conditions.

Insulin/BG deals with the energy appetite stimulus provides. But what do I know.

the carbohydrate-insulin-fat hypothesis is not generally considered viable by the scientific communityI'm genuinely curious as to how you determined this. Is it your opinion or a demonstrable fact? Or does it just depend on who's works you read?

“They found that insulin sensitivity of fat tissue declines as the size of fat cells increases. This was true across all cell sizes, not only the largest ones. As body fat gain mostly involves an increase in fat cell size rather than number, this suggests that fat tissue insulin sensitivity progressively declines as fat mass increases.”

Under the dynamic equilibrium model, of which the balloon of my earlier post is a naïve example, this is exactly what you would expect.

“But they went further. They caused weight loss in their obese subjects using a calorie-restricted diet (15:45:40 protein:carb:fat), which shrunk their fat cell size. Following this intervention, insulin sensitivity in fat tissue increased, …”

Again, exactly what a dynamic equilibrium model predicts. Deflate the balloon a bit and it becomes easier to pump air into it.

“… and both the blood glucose and insulin response to an oral glucose load improved considerably. They concluded:

Careful here, though. BG and insulin response to a glucose challenge are going to depend more on the insulin sensitivity of the skeletal myocytes and hepatocytes, as primary consumers of glucose, rather than on the insulin sensitivity of the adipocytes.

So, these data are consistent with the idea, which finds support in the literature, that obesity can contribute to whole body insulin resistance, for example by leading to intramyocellular lipid accumulation that interferes with insulin signalling in the skeletal muscles, but they cannot distinguish between this as a feedback loop in a process that ultimately has another cause (e.g. myocellular mitochondrial dysfunction), or as the underlying cause itself. Neither can they exclude the possibility that the dietary change restored whole body insulin sensitivity by another mechanism altogether.

Thank you, Stephan Guyenet. As you said, you've proven the hypothesis that carbs cause weight gain independent of calories wrong to anyone capable of looking at evidence. I'd love to get your take on other topics; you genuinely have one of the best diet blogs i've seen.

Do you have an opinion on people who are claiming to gain muscle on an 80/10/10 carb/prot/fat diet?

Donald, don't be depressed. It's terrific that VLC worked so well for you. Many of the folks arguing with Taubes over the actual origin of obesity have said that they feel that once you are obese/insulin resistant, then reducing carbs is a good strategy to lose weight.

That said, I do think this discussion is helpful. Consider the possibility that going VLC is essentially over-swinging the pendulum and that perhaps that level of carb restriction may not be required. Maybe it's the wheat, maybe it's the sugar, maybe it's the high reward processed foods that a VLC diet omits that are the real culprits (or maybe it's something else).

It's worth it to keep digging at the issue so we can identify all the important factors in obesity (this is not a one-size-fits-all condition). After all, not everyone wants to (or can or should) stay on VLC perpetually.

“The fat loss coupled with unchanged basal metabolic rate means that either a) diazoxide made them start exercising a lot, and/or b) they ate less. It was almost certainly (b). So did reduced insulin action on their fat cells make them eat less? Given that fat cells don't regulate food intake (except indirectly via their production of leptin, which acts in the brain), and the brain does, perhaps we should shift our focus to the brain for a moment.”

Second, if the insulin hypothesis is correct, reduced insulin would result in increased release of FFAs from the adipose tissue (and we can’t tell whether that happened). If it did, FFA availability may have had an appetite-reducing effect:

http://www.ncbi.nlm.nih.gov/pubmed/20232053

So, did reduced insulin action on their fat cells make them eat less? Maybe.

Your analogy makes sense, but it doesn't explain anything further--or, actually it kind of implies Taubes has an inadequate explanation, but not that he's necessarily wrong in what he does say. But you are implying that too much insulin is the cause. Does ffa availability itself decrease appetite or is it the oxidation?

Insulin secretion inhibition, however done, does often cause fat loss, and obese SC fat cells have lower HSL expression. But obese people [compared to lean] in response to a meal do more glycogenesis and less DNL, depsite higher insulin responses. Obese people's muscles oxidize more glucose during fasting and more fat after eating/overeating.

...Something is off here: they have available fat (or do they?) that's not being used [glucose is], but they're supposed to be insulin resistant. So their insulin action is "overpowering" any resistance during fasting, but not after they eat?

Stephan,

Do you think responses to meals in the overeating Massas are different than the typical obese American?...Do they have exaggerated insulin responses and lower postprandial RQs compared to lean?

That's the trouble with analogies (which this was not supposed to be): they have no explanatory power.

I'm not sure about Taubes: I listened to his interview on Latest in Paleo and I think he's shifting his ground a bit; beginning to distinguish between the metabolically normal and the metabolically broken.

That said, the carbohydrate part of the carbohydrate/insulin hypothesis is looking rather shaky to me and Stephan has done a good job of exposing its limitations, at least as an explanation of "why we GET fat". The insulin part still seems to be intact from my perspective, so Taubes's ideas may still offer insights into "why we STAY fat" and why carbohydrate restriction may be a part of the solution.

Stephan,Any chance of this blog going back to its roots of talking about traditional cultures and overall health instead of being just about obesity?

Don't get me wrong, your posts, as always, are very well written,referenced and clearly informative for the layman. But for those of us who realize that it isn't just Carbs or fats or the boogeymonster that causes obesity and that a diet of natural whole foods with exercise is probably the best way to lose weight, well, these posts, while still great, seem to displace some other potentially interesting topics like heart disease, fructose, gut dysbiosis, etc... Anyways, Im not saying you shouldn't blog a out obesity ever again but instead, as the educated and smart researcher that you are, I'm always curious to read your thoughts on other topics.

Most low carbers have tried "healthy" carbs and realized they simply don't work. People don't follow the diet blindly, they experiment. They cut all carbs at first, then they do exceptions and then realize that popatos and fruits are as bad as bread for them. I know that peanuts are too much carbs for me. I think it depends on how screwed your system is. Maybe after years on very low carb I could "heal", or maybe it's too late for me. I'll centraly try potatos (again) afer I'm feeling more confident.

Many (lean) people think that the word "craving" or the word "hunger" mean the same thing for them as they do to fat (carb sensitive) people. I've experienced it and I can say that if you are sensitive you kinda lose the notion of what "hunger" or "satiety" are, completely.

The fatty acid releasing fat cells of obese people do not contradict the carb-insulin-obesity hypothesis because the fat cells have reached their capacity fat-storage-wise. If this happens, new fat cells will be created to store the extra fats.

The number of fat cells in a human body is not constant, and I bet having a high insulin level and leaking fat cells is a good condition to start adding new fat cells.

It seems to me that insulin is either going to be a pro-obesogenic factor or it's going to end up like the raining outside-umbrellas analogy.

This insulin vs. food reward is mildly productive, but I think we all know that it's not that simple and the only benefit we are getting from the debate is to re-examine information and gain new insight that will lead us to a new hypothesis.

This post is precisely what Taubes is addressing in his Part I. Stephan is caught in the paradigm of the current science of nutrition. This idea of insulin resistance, maybe it's completely useless. Proving or disproving the effect of insulin or insulin resistance on obesity might have nothing to do with what we're trying to figure out. It may be that the measures we have are hardly significant, or the ways we are looking at them will not lead anywhere.

If Stephan makes a large and convincing (to others) post debunking the insulin hypothesis of obesity, I'm just going to trust him. I don't have the understanding of the science nor the desire/time to research myself when I'd probably just waste a few years to say that he was right. But to go further and almost make it seem like the insulin hypothesis is way off seems minimally productive.

When you say "Obese people's muscles oxidize more glucose during fasting and more fat after eating/overeating" what do you mean? That they're oxidising more serum-derived glucose, or that they're oxidising more glucose derived from muscle glycogen? The difference is that serum glucose has to overcome the insulin resistance in the GLUT-4 channel (doi:10.1152/physrev.00024.2006), whereas muscle glycogen does not: it's already there.

You might expect glycogen-derived glucose oxidation to be greater in the fasting state, because glycogenesis is increased in the postprandial state, and glycogen is a finite store. That doesn't explain anything, but it does at least show that the observations are consistent.

I meant that the obese have higher fasting RQs and lower post-prandial (at least with a carb meal) RQs. I was going to ask Stephan if and how obese people's glycogenolysis and gluconeogenesis differ from lean.

From table 2 of your reference, serum glucose uptake is about the same in lean and obese, but oxidation is higher in the obese. Then, to quote: "The negative values for net storage are indicative of glycogenolysis during postabsorptive conditions. The negative values for net glucose storage were greater in obesity (-0.12 +/- 0.10 vs. -0.35 +/- 0.06 µmol/min/100 ml leg tissue; P < 0.05)"

So, the increase in fasting oxidation is down to glycogenolysis, as I suggested, thus bypassing the insulin resistance in the GLUT-4 channel.

To your question: "So their insulin action is "overpowering" any resistance during fasting, but not after they eat?" Maybe the answer is no, because after they eat the increased oxidation is by means of a process that isn't affected by the (GLUT-4) insulin resistance.

This whole debate is well above my pay grade, so to speak. I'm merely a curious, formerly heavy person with no background in the biochemistry of metabolism who is interested in this stuff from the perspective of figuring out how I stay thin, and avoid diabetes.

When Stephan says this: "I have pointed out the reasons why the carbohydrate-insulin-fat hypothesis is not generally considered viable by the scientific community" it sure sounds like the notion that carbohydrate drives insulin drives fat idea was fabricated from whole cloth.

But the debate did make me curious about the actions on insulin in the body, and so I glanced through a couple of web sites that are devoted to the biochemistry of metabolism. It truly is a complex subject.

A section on this page (http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html) really got my attention:

"From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue."

So I can understand why someone looking at this from outside might be tempted to conclude that chronic elevation of insulin from over consumption of carbohydrates might play a big role in obesity. Is Stephan trying to say that this statement from a basic primer on the biochemistry of metabolism is wrong? What am I failing to grasp here (in simple, layman's terms)?

You state "The idea that insulin acts on fat cells to promote obesity requires that insulin suppress fat release in people with more fat (or people who are gaining fat) to a greater extent than in lean people."

I don't understand why you think this is true. It seems to set up a straw man position. The theory that higher insulin levels promote obesity does not require that insulin sensitivity improves with increasing obesity. It requires only that the basal or average insulin levels of the obese are higher than those of the non-obese. In fact, it is natural or expected that the "margin" sensitivity of insulin decreases with increasing obesity and insulin levels, allowing for "spilling" of excess fatty acids as a homeostatic regulatory effect.

There is another misconception running around here. Somehow, opponents of the carbohydrate/insulin hypothesis of obesity seem to think the theory claims that carbohydrates and insulin are a SUFFICIENT condition for obesity. Understood correctly, carbohydrates are NECESSARY BUT INSUFFICIENT condition for obesity. Thus, the existence of individuals and populations who eat a very high carbohydrate and remain lean does not represent a counterexample. In fact, these populations and individuals typically have low basal insulin levels. I will agree that a high carbohydrate in and of itself does not cause hyperinsulinemia. You must have insulin resistance for that to happen.

The other necessary conditions for carbohydrates to be obesogenic are likely to be inflammatory factors in diet, environment and genetic predisposition that lead to insulin resistance. These factors are probably independent of carbohydrates as a general class, though certain carbohydrates, e.g. fructose and sucrose, may promote insulin resistance. Certain fats and anti nutrients, deficiencies (Vitamin D, magnesium) and environmental stressors may also promote IR.

Those who are insulin sensitive due to genetics, youthful age and a noninflammatory diet (as the Kitavins, Okinawans, etc.), would thus not be expected to get obese from eating healthful carbohydrates, even at high levels.

This also explains two other phenomena: (1) The obese IR individuals can lose weight by cutting out carbohydrates, since these are one of the three necessary conditions for obesity; (2) Cutting out pro-inflammatory fats and anti nutrients -- basically going "Paleo" -- provides an entirely independent way to lose weight.

In short, I think that recognizing that a high carbohydrate diet, insulin resistance are each necessary, but insufficient preconditions for obesity reconciles some of the paradoxes and disagreements between you and Gary Taubes. I do believe that each of the "camps" are looking at different parts of the elephant, talking past each other, and overlooking a more comprehensive picture of obesity.

Great post Stephan. Diazoxide decreased fasting insulin by 36 percent, and this had no effect whatsoever on fat burning or resting energy expenditure. This is a very strong point in support of your argument, but how about an equally strong point against it? What if 1) “fasting insulin” should have included the postprandial period, but they only measured morning levels, and 2) “resting energy expenditure” was only in the morning. Energy expenditure could be increased postprandially, but this wouldn’t be reflected in morning energy expenditure. So the effect was due to the lower “postprandial” insulin levels, which coincided better with total energy expenditure, as opposed to the morning insulin levels, which were only related to morning energy expenditure.-Bill

And as long as we're here talking about how the brain is in control of fat mass, wouldn't it also be in control of muscle mass? Has anyone identified brain signals or hormones which activate muscle growth? Are these part of the reward cycle too?

I'm not sure what insulin hypothesis everyone else is reading, but the one that Taubes is putting forward is as follows:1) Elevated fasting insulin suppresses lipolysis, increasing the settling point of the fat mass2) Cells feel starved3) Body signals to the brain that it's hungry4) We feel compelled to eat more

In this post and others, Stephan has thoroughly debunked part one of this proposed mechanism of action. The fact that the fat cells of obese people are insulin resistant should be enough to prove this, but since for some of you it's not, Stephan cited an example in which insulin was artificially lowered through a drug intervention and BMR remained unchanged. Extra fat is not being oxidized as a result of the insulin levels going down, meaning that either extra fatty acids are not being released, or if they are, they are being reincorporated without the action of insulin.

No one is saying that insulin is not involved in fat metabolism. It clearly is. But it is involved as the slave in the master-slave relationship. It is an effect downstream of a cause.

That is not to say that there is not another mechanism by which low carbohydrate dieting could be uniquely effective in helping some individuals lose weight and/or keep it off, only that the proposed mechanism is wrong. A couple people in the blogosphere, including J Stanton, have been pointing out some interesting experimental findings with respect to fat oxidation in obese vs lean individuals, and the proportion of calories burned during fast periods as fat and carbohydrate. Maybe this will prove to be a factor at some point, maybe not.

You don't actually need to know what's going on inside a black box system in order to empirically determine what inputs get you favorable outputs. However, as we get more insight into how the black box works, we can become more targeted and effective in our approach. Taubes has done a lot for all of us insofar as he introduced many of us to the ancestral health community, but it is time to put his debunked mechanism to bed in favor of one that actually fits the empirical data.

Let me try to explain it a different way. The idea, as stated by Taubes, is that 1) insulin goes up, 2) lean tissues become insulin resistant, 3) fat tissue remains insulin sensitive, therefore 4) insulin action on fat cells is increased, and this leads to 5) fat accumulation.

The scientific literature shows that fat tissue progressively becomes insulin resistant as it expands. In fact, the insulin resistance of fat cells if anything outpaces the increase in fasting and post-meal insulin. Therefore, insulin action on fat cells if anything is gradually reduced as fat accumulates. This is the opposite of what the hypothesis would predict.

Couple this with the fact that insulin is not rate-limiting for fat oxidation, and I don't see the theoretical basis for this hypothesis.

Some of the people aren't trying to defend Taubes specifically. Stephan pointed out a study that contradicts another study that does support insulin hypothesis. The comment about fat cell insulin resistance isn't absolutely true because they do do less lipolysis per unit fat mass, and they have less HSL expression. And despite what I said earlier, they also tend to do more DNL. So, it's not really as clear-cut as you seem to imply.

You said, "You don't actually need to know what's going on inside a black box system in order to empirically determine what inputs get you favorable outputs."

Okay, but some people like to know what's going on to have a good idea of what works, without having to first empirically determine it--I guess this mostly revolves around the desire to eat certain carbs.

I guess Stephan's point that "...the insulin resistance of fat cells if anything outpaces the increase in fasting and post-meal insulin," is actually pretty important to consider though--maybe I'll just go back to leaving the black box alone.

Thanks for your reply, Stephan. I should reiterate that I'm not trying to defend Taubes' whole story (what I call the "strong" carbohydrate/insulin hypothesis, only one key part of it: that under conditions of pre-existing IR, carbs + insulin drive obesity. I agree with you that neither carbs nor insulin themselves cause insulin resistance. (That is where I depart from some of Taubes' and Eades' claims). Insulin resistance has other causes, e.g. inflammatory diet and lack of exercise -- as you have so aptly pointed out. But once insulin resistance is in place, hyperinsulinemia often follows, and this condition acts to inhibit lipolysis. Over time this sets up a trajectory of obesity. Thus carbs + insulin are necessary, but not sufficient, for obesity.

All that this "weak" hypothesis requires is that adipose tissue be relatively more insulin sensitive at the outset than other tissues like muscle and liver. It is fully consistent with adipose tissue becoming less insulin sensitive as one becomes more obese.

Your above post did not address this possibility, and thus does not establish that the decreasing insulin sensitivity of obesity is "the opposite" of what would be predicted by my "weak" version of the carbohydrate/insulin hypothesis. (I hold that high insulin levels and carbs are necessary but not sufficient for obesity; the other requirement is IR). I would really like you to respond to this specific objection.

You also mention that that "insulin is not rate-limiting for fat oxidation". I don't see how that makes any difference, once you adopt the "weak" version of the carbohydrate/insulin hypothesis, as I have stated it above. Maybe I'm missing something -- perhaps you could explain.

Geoff,

I happen to agree with you that "cells feel starved" is a weak point in the standard "strong" account of the carb/insulin hypothesis. But I do think that a high carbohydrate diet in a background or pre-existing insulin resistance and associated leptin resistance can explain the intensified appetite and carb cravings of obese IR individuals. Lustig has documented that obese IR individuals typically have CNS insulin and leptin resistance. Unlike lean individuals, where insulin and leptin readily cross the blood-brain barrier, this mechanism is impaired in the obese. Thus, insulin induces peripheral hypoglycemia postprandially, which increases appetite and is not counteracted by the normal satiating effect of insulin action on the hypothalamus.

I think this fact provides a more plausible explanation that "hungry cells" for the appetite drive caused by a high carbohydrate diet in insulin resistance individuals.

My weakened version of the carb/insulin hypothesis also explains why the Kitavans, Okinawans and other insulin sensitive populations remain lean and healthy on a high carb diet.

I do think it is very likely that Taubes has got steps (1) and (2) of Stephan's five steps in the wrong order, and step (3) really ought to say "relatively insulin sensitive", but I don't think your "weak" version has been invalidated at all.

Gunther gatherer said, "And as long as we're here talking about how the brain is in control of fat mass, wouldn't it also be in control of muscle mass? Has anyone identified brain signals or hormones which activate muscle growth? Are these part of the reward cycle too?"

Yes we know those pathways. Those are the AMPk pathways and leptin pathways in the brain and how they effect MTor centrally and peripherally. Here is a brief primer on it.

Yes, you and I agree about the dynamic equilibrium in which insulin resistance increases with hyperinsulinemia, but there is still enough inhibition of lipolysis to maintain obesity. If that were not true, the obese person would suddenly become lean again! (Of course, in advanced diabetes, this can actually happen when the pancreas finally gives up).

I also really liked your balloon analogy, because it demonstrates the idea of balancing forces. To take it further, the advanced diabetic who can no longer make insulin would be like a popped balloon.

...actually re-reading your balloon analogy, a better analgoue of the IR to Type II diabetes transition is when the air pump finally gives out and the balloon deflates. No popping is involved, because your baloon already has a leak in it.

You said: "... but there is still enough inhibition of lipolysis to maintain obesity. If that were not true, the obese person would suddenly become lean again!"

Perhaps this was what Stephan meant by "outpaces"? But if so, it's an unphysical situation. You don't go from a state in which the net flow of fatty acids is into the fat cells (e.g. after an increment in insulin levels), to one in which it's going the other way (insulin resistance overpowers the insulin effect), without passing through the intermediate state where there's no net flow, and once you reach that state, that's where you stay - and you're a bit fatter.

Your grouping of "pre-existing insulin resistance and associated leptin resistance" is a little odd because all obese people are leptin resistant and some of them are insulin resistant. It would appear that it is the IR that is "associated" with obesity whereas the LR is probably causal. Chris Masterjohn did a great post on this here: http://blog.cholesterol-and-health.com/2010/11/is-insulin-resistance-really-making-us.html.

Your "weak" hypothesis is that under conditions of pre-existing muscular (and liver) insulin resistance, dietary carbohydrates drive obesity by increasing insulin. I have some major criticisms of this point that you're going to have to address for yourself if you want to consider it viable.

First, obese individuals defend against fat mass increases in overfeeding studies. If your mechanism were viable, this would not be the case. I suppose that this is a serious criticism of any "settling point" version of a theory of obesity, of which your "weak" carbohydrate-insulin hypothesis is a part. If this mechanism of action were real, that is not what we would observe. Instead, we would observe a near one-to-one relationship between overfeeding carbohydrates and weight gain. In other words, for every 3,500 kcal above BMR consumed, we should see an extra pound of body fat. Instead we see an upregulation of metabolism to deal with this excess consumption, resulting in underwhelming results in overall weight gain. The discrepancy can be quite large, up to thousands of kcal per day in some instances if I remember correctly.

Second, where fuel is stored in the body doesn't actually matter if it all gets burned off. All excess calories get stored as fat (after glycogen stores are filled) whether you eat high carb or low carb, what makes us fat is the compulsion to eat again and the subsequent action of actually doing it. This is why Stephan's point about insulin not being rate limiting in fat oxidation matters. Just because calories are stored in the fat tissue doesn't mean they are not available to be burned as fuel.

Taubes is saying that the cells of the body feel starved because elevated fasting insulin inhibits lipolysis, which prevents the cells from getting access to the fatty acid fuel that they need, which drives hunger. In reality, that is not what we see. Fatty acids can and do get out of the fat tissue.

Why they are not being oxidized at the same rate as in lean individuals is another question altogether, but I don't see how it is in any way related to insulin, and it is not clear to me that this discrepancy between the lean and obese actually results in cells experiencing energy shortages. We do see a decrease in activity relative to lean people, but is this due to cells feeling like they don't have the energy or is it due to the brain thinking that leptin levels are low as a result of the hypothalamus being insulin resistant and the setpoint being elevated?

If it's because of the former, then how do the cells communicate back to the brain? Maybe once they've pulled enough glucose out of the bloodstream, the brain sees the low glucose levels, as you suggest. But do the obese actually become hypoglycemic between meals? Because I'm pretty sure that they are generally hyperglycemic, i.e. they have high fasting blood glucose. You're saying that a hypoglycemic dip between meals causes overeating, but as far as I know that doesn't actually happen.

Then there's the question of the obese, IR individual losing weight eating carbs, whether it be the plain liquid diet, the potato diet, some typical starvation diet or something else.

I think herein lies the puzzle. When fat cell is inflated due to increased calorie/fat intake, free fatty acid (FFA) concentration is increased to to increased leakage from fat cell, by what mechanism is it sensed that FFA concentration has increased in blood plasma and that an increase in circulating insulim should insue to force fat into the fat cell.

In other words:-Fat intake in meal --> Increased FFA in blood plasma --> Increase circulating insulin to shunt fat into fat cell as fat cell now needs a new higher insulin threshold to hold fat at the new infalted size.

It implies that fat intake should have an insulin response. But we know fat intake does not cause an insulin response (or atleast to my knowledge).

By what mechanism are fat levels sensed in blood stream? Does the body try to keep them within narrow limits like blood glucose?

I think herein lies the puzzle. When fat cell is inflated due to increased calorie/fat intake, free fatty acid (FFA) concentration is increased to to increased leakage from fat cell, by what mechanism is it sensed that FFA concentration has increased in blood plasma and that an increase in circulating insulin should insue to force fat into the fat cell.

In other words:-Fat intake in meal --> Increased FFA in blood plasma --> Increase circulating insulin to shunt fat into fat cell as fat cell now needs a new higher insulin threshold to hold fat at the new inflated size.

It implies that fat intake should have an insulin response. But we know fat intake does not cause an insulin response (or at-least to my knowledge).

By what mechanism are fat levels sensed in blood stream? Does the body try to keep them within narrow limits like blood glucose?

The arculate nucleus in the brain does an excellent job of integrating appetite signals from both hormones and energy molecules.The arcuate nucleus in the brain, inclucing sensing changes in both glucose and FFA: http://bit.ly/pSqA55

"[T]he arcuate nucleus responds to swinging blood sugar levels, appetite being stimulated when blood glucose levels fall and inhibited with the high blood sugar levels encountered after a meal. The secret to this is the presence of glucokinase (GK) in the arcuate nucleus."

and

"the circulating levels of fatty acids are an excellent signal of the total metabolic situation, and the LCFACoA formed in the arcuate nucleus dampen appetite and reduce food intake."

"'First, obese individuals defend against fat mass increases in overfeeding studies. If your mechanism were viable, this would not be the case.'

Why not? The hypothesis does not hold that every "spare" calorie must be driven into the fat cells. Just some of them."

Every spare calorie does get driven into the fat cell. That is not really debatable. Your food does not circulate around in your bloodstream until it's all been used up. The question is not whether the excess gets stored as fat, but whether it gets burned off after. Under your proposed mechanism of action, it gets stuck there because insulin inhibits lipolysis in IR individuals.

Maybe you can explain how under this mechanism the body would defend against these changes. Where does the signal come from that says "hey cells, this guy is eating like a jackass, we need to run a bunch of futile cycles and make him fidgety to get rid of it." It's certainly not obvious, and as best as I can tell there is no plausible mechanism by which this would occur. In fact, the mechanism you are proposing basically makes it impossible for this to occur, if true.

Under the leptin setpoint model, the fuel gets stored as fat, which results in the fat cells producing more leptin, and the brain sees this extra leptin and upregulates metabolism to burn the extra fat off.

"'Just because calories are stored in the fat tissue doesn't mean they are not available to be burned as fuel.'

It depends what you mean, but it is certainly true that if the calories are stored in the fat tissue they are not in fact being burned."

I mean that under your model, once calories are stored as fat, they are inaccessible to the body. Yet in reality, even in people with hyperinsulinemia, lipolysis occurs. Fatty acids are being released and burned. Fuel in the fat tissue is accessible as needed. As Stephan said, insulin is not a rate limiting factor in fat oxidation.

To your third question, the fact that you are so sure that people with muscular IR get hypoglycemic between every meal is making me less certain that they don't, but I do know that hyperglycemia is common among obese individuals, and that there is a level where it is called "pre-diabetes" even though pancreatic beta cells are still secreting insulin. Hopefully someone more knowledgeable about the biochemistry can answer better.

I agree that satiety signals from fat, protein and glucose are initiated by the hypothalamus. My question was how is insulin raised in response to free fatty acids (FFA) in plasma i.e. after eating.

The way I see it is like this:1. Fat cell becomes insulin resistant as it stores more fat and requires more circulating insulin to keep the fat in itself.2. Insulin is only increased in response to high glucose concentrations by beta cells.

I hypothesize that increased FFAs are sensed by the brain which then makes the liver (and perhaps muscle) insulin resistant via the vagus nerve. The insulin resistant liver releases excess glucose in the blood stream. In response to increased glucose, the beta cells increase insulin. The increased insulin then shunts excess FFAs into the increasingly insulin resistant fat cell due to its increased size.

It may not be a perfect theory but increased insulin, glucose and enlarged fat cells (obesity) all go hand in hand.

As for low-carb diets, as long as net calorie intake is less than daily calorie expenditure, fat cells will reduce in size corresponding to a lower insulin resistance and due to lowwer FFAs in blood, brain will reduce insulin resistance of the liver to deliver lower glucose levels and a consequent low insulin production by beta cells.

I think your explanation, or something like it, is probably right. FFA has no direct effect on insulin, but can increase insulin resistance, which tends to amplify any subsequent insulin response.

@ Geoff

Thanks for linking to the excellent Masterjohn post. You may be right that leptin resistance is a more proximate cause of obesity, and is more reliably linked to it. So I might modify my hypothesis to say that, obesity requires carbs + hyperinsulinemia. Normally this is associated with IR. But even if not, Lustig's analysis indicates that "hyperinsulinemia may be a proximate cause ofleptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity".

http://bit.ly/qJBxEl

So while some obese may be relatively insulin sensitive, they would still likely benefit from carb reduction and insulin reduction, as this would improve leptin sensitivity.

I just wanted to make it clear that I believe that the brain is central to inducing insulin resistance in the liver and fat cells. There is neural interface in the production of adiponectin from the fat cells. I believe that fat cell insulin resistance has many components: fat cell size and signals from the brain to make it insulin resistant both via independent mechanisms/paths. That is why insulin resistance drops dramatically post small intestine obesity surgery even when fat cells haven't reduced their size or flooded the plasma with FFAs.

Individual cells (liver, beta cells, muscle and fat) may have their own mechanism of becoming insulin resistant but the brain has the biggest influence of all and can greatly influence the insulin resistance threshold of many different types of cells.

When I said that the hypothesis does not hold that every "spare" calorie must be driven into the fat cells, I meant that the hypothesis does not exclude the upregulation of metabolism to burn off some of the extra calories in response to overfeeding.

Insulin is not a rate limiting factor in fat oxidation may be true, but it appears that insulin does inhibit fat oxidation.

http://www.jci.org/articles/view/17303

:: "Thus, hyperinsulinemia, such as that which normally occurs after meal ingestion, drastically limits the availability of FFA to muscle, further inhibits LCFA oxidation even if LCFAs enter the cell, and makes available more glycerol-3 phosphate for LCFA esterification into triglyceride."

Finally, it's not that I think that people with muscular IR get hypoglycemic between every meal. I don't believe that. But it seems likely that they are relatively hypoglycemic when in the fasting state and it is plausible that that may play a role. There's some evidence that the glycemic level at which the brain initiates its hypoglycemic response depends on the level of circulating insulin too, so what may not be hypoglycemia in a healthy person may, effectively, be hypoglycemia in a hyperinsulinemic individual:

As far as I know, many people experience "hypoglycemia" with high blood glucose, so the fact that obese people may or may not truly have high blood glucose between meals doesn't exclude them from falling victim to hypoglycemic symptoms followed by eating...

Quick question--seeing as how insulin has been vindicated, more or less, who is the conductor on the train to hell? More clearly--who should I be blaming when i get fatigued after eating a high carb meal (coming from whole foods)?

Also, if it's possible, is there anyone who can compile a list of necessary foods we should be eating, nutrient wise? I feel like this is a more logical way of compiling a healthy way to eat (i.e. eat liver once/twice a week, make sure to get eggs daily for choline, tubers for vit c..etc); the "goodness" (or badness) of calories seems to be determined by the nutrients they shuttle in, and the predominance of macronutrients (high/low carb) should be controlled by these very conditions (i.e. certain macros being more beneficial in their ability to transport certain micronutrients--indirectly through a mechanism such as insulin, or directly through the intrinsic nutrient stores of such foods)

Thanks from me too for the link to Chris Masterjohn’s leptin post. Food for thought indeed.

There's no doubt leptin plays a significant role in all this.

When I first read Chris's commentary on the LIRKO mice, I thought, “RIP insulin hypothesis.” But then I thought, hang on, is he right when he says, “So if high insulin levels are what act on our adipose tissue to make us fat, these mice should be really, really, really fat?”

Even if you adopt the position that the insulin hypothesis describes everything as far as overall fat mass is concerned, you still don’t conclude that higher insulin (in the LIRKO mice) implies higher fat mass, because insulin is only going to promote fat storage if there’s fat to be stored. In other words, you would expect the rate of fat storage to depend on insulin, yes, but also on the levels of circulating TGs and FFAs, and in the LIRKO mice, TGs and FFAs are about half what they are in the controls.

At a naïve level, you might then think that the insulin-promoted influx of FFAs into the fat tissue is going to be about half what you would expect so see in the controls. How would that explain away a seven-fold increase in fasting insulin? The answer could be that the reduction in plasma TGs and FFAs results in a huge increase in the FFAs leaving the cells because of an enormous change in the relative concentrations of FFAs on either side of the cell membrane.

Go back to my balloon “analogy” and imagine that the pump is running along nicely and keeping the pressure inside the balloon about 20% higher than atmospheric. Let’s say that maps onto a normal individual with normal insulin levels.

Now, what happens if you suddenly reduce the external air pressure by 50%? Answer: the pump is now only half as efficient and the pressure difference across the skin of the balloon goes from 20% of an atmosphere to 70% of an atmosphere: 3½ times as much. By how much do I need to increase the work rate of the pump to keep things as they were? By a factor of seven.

So, it is by no means clear that the increased insulin levels in the LIRKO mice should be obesogenic if the insulin hypothesis is correct, because you have to take into account the other changes (including plasma FFA and TG concentrations) as compared with the controls.

I explain everything related to insulin in that post by the following: leptin resistance causes obesity and insulin resistance. Stephan made a great analogy in the comments on another post somewhere. Imagine the body is a car. In this car, insulin would be like the wheels, leptin is the engine, and the hypothalamus is the driver. So while the car cannot drive without the wheels, which is like a type 1 diabetic trying to store fat, it is not the wheels that drive the car. In fact it isn't even the engine, although the engine does power the wheels. It is the person pushing the gas pedal that drives the car.

To the question of hypoglycemia, again, I really don't know enough about it to comment, but people who are hyperinsulinemic, as far as I know, usually or always have high fasting glucose. The question is what causes this high fasting glucose, and I don't think that dietary carbohydrates are a good explanation for this. There are too many counter examples. I think that the neolithic agents of disease are a better explanation, and I am including hyperrewarding properties in there as the fourth NAD, though I suspect that it is possible that at the end of the day, it may turn out that the hyperrewarding foods are the NADs, particularly linoleic acid and wheat.

You still have not explained how the body of an obese, IR individual goes into overdrive in response to overeating if it is insulin driving fat storage in response to dietary carbohydrates rather than the brain in response to elevated leptin levels in the blood. This is the major problem with settling point theories of obesity. They explain what prevents the level from going down, but they don't explain what prevents it from going up.

I agree with you that excess dietary carbohydrate is an unlikely explanation of fasting hyperglycaemia, but I don't see the relevance of that to Todd's “weak” hypothesis.

As to postprandial thermogenesis in the obese, in a previous post, you suggested that the mechanism is something like: excess calories → fat storage → increased leptin → thermogenesis. What I don't understand is how this excludes the insulin hypothesis. How about: excess calories (some of which are carbohydrate) → BG excursion → insulin secretion → fat storage → increased leptin → thermogenesis? I don't say this is what happens, I say it is not inconsistent with your ideas. Also bear in mind that leptin is secreted by the peripheral tissues in response to nutrient sensing: excess calories → increased leptin → thermogenesis.

I'm not here to defend the insulin hypothesis because I believe in it; I'm saying that many of the arguments that have been deployed here (like the insulin resistance argument) to demolish it, do not. To that extent, they get in the way of an objective assessment and I don't think that's helpful.

"For example, how does your model explain the release of fuel from the fat cells, mechanistically?"

There are probably a number of ways this happens, but ultimately, the hypothalamus decides whether to release fat or not based on what it thinks is going on in the body. Again, I would say that the "weak" form of the insulin hypothesis put forward has much more problems explaining the release from fat tissue, because somehow the body needs to get access to this fat in spite of the elevated insulin inhibiting lipolysis.

It excludes the insulin hypothesis because it posits that insulin is a slave in a master-slave relationship. Insulin is the hammer, not the guy swinging it.

A better way of expressing my point about Chris Masterjohn's post is this.

From his ref. 13: They [the LIRKO mice] also display focal dysplasia and hyperplastic nodules in their livers and a 50% reduction in albumin levels, as well as a similar reduction in serum triglycerides and free fatty acids (9, 10), which could be explained, at least in part, by the inability of insulin to promote triglyceride synthesis in liver ...

If there's little triglyceride synthesis, there will be far fewer chylomicrons and thus there will be far less substrate for the action of LPL. This will considerably blunt the efficacy of insulin to promote fat accumulation, so the high insulin levels would not necessarily be expected to result in obesity.

1. Geoff: “Imagine the body is a car. In this car, insulin would be like the wheels, leptin is the engine, and the hypothalamus is the driver.”

Todd: I fail to see how this analogy explains obesity. Obesity is not caused by excess insulin or leptin, but rather by insensitivity (“resistance”) to insulin and leptin (in combination with an insulin stimulus like carbohydrates). There is no exact car analogy, but it would be like a car with a plugged or leaky fuel valve that responded slowly and inefficiently to the accelerator, so it would “grow” a larger gas tank and waste gas trying to get up to speed or something. This inefficiency “explains” why the driver pushes the gas pedal excessively. There is no need for psychological postulates about the driver.

2. Geoff: “…people who are hyperinsulinemic, as far as I know, usually or always have high fasting glucose. The question is what causes this high fasting glucose, and I don't think that dietary carbohydrates are a good explanation for this.”

Todd: I agree that dietary carbohydrates don’t cause hyperinsulinemia or hyperglycemia. The cause of elevated blood glucose is no mystery: Insulin resistance reduces the number and efficiency GLUT4, allowing glucose levels to rise. The pancreas upregulates insulin secretion to counteract this to some extent, but process is still inefficient. Once IR is in place, however, carbohydrate ingestion maintains obesity by not allowing basal insulin to fall.

3. Geoff: “You still have not explained how the body of an obese, IR individual goes into overdrive in response to overeating if it is insulin driving fat storage in response to dietary carbohydrates rather than the brain in response to elevated leptin levels in the blood. This is the major problem with settling point theories of obesity. They explain what prevents the level from going down, but they don't explain what prevents it from going up.”

Todd: It’s not either/or. It is the combination of IR and carbohydrates that drive obesity. The weak insulin hypothesis holds only that high carbohydrate consumption is a necessary condition; insulin- (and leptin-) resistance are also required to drive obesity.

You claim that leptin resistance, not insulin resistance is the driver (or at least a necessary condition) for obesity. However, experiments by Lustig suggest that hyperinsulinemia causes leptin resistance:

http://bit.ly/r0BpDV

By administering an insulin agonist (octreotide-LAR) to obese adults, he reversed their hyperinsulinemia and secondarily their leptin resistance, leading to dramatic weight loss. This is a pretty strong demonstration of the essential causal role that hyperinsulinemia (which results from IR) plays in obesity.

4. Geoff “ultimately, the hypothalamus decides whether to release fat or not based on what it thinks is going on in the body. Again, I would say that the "weak" form of the insulin hypothesis put forward has much more problems explaining the release from fat tissue, because somehow the body needs to get access to this fat in spite of the elevated insulin inhibiting lipolysis.”

Todd: The hypothalamus’ “decision” about whether to release fat is governed by how much leptin crosses the blood-brain barrier. Hyperinsulinemia impairs detection of leptin, so the body holds onto fat. This is a direct consequence of the weak insulin hypothesis, which holds that both carbohydrates AND insulin resistance are required for obesity. While hyperinsulinemia thus “inhibits” lipolysis and fat oxidation, it certainly doesn’t shut it down. This inhibition becomes progressively inefficient in advanced obesity, while still being sufficient to maintain obesity. – as Strontium’s “balloon” analogy nicely illustrates. However, if you administer ocretotide or another insulin agonist, obesity disappears!

The weak insulin hypothesis is consistent with all the above facts, so I see no reason to abandon it at this point.

1. Geoff: “Imagine the body is a car. In this car, insulin would be like the wheels, leptin is the engine, and the hypothalamus is the driver.”

Todd: I fail to see how this analogy explains obesity. Obesity is not caused by excess insulin or leptin, but rather by insensitivity (“resistance”) to insulin and leptin (in combination with an insulin stimulus like carbohydrates). There is no exact car analogy, but it would be like a car with a plugged or leaky fuel valve that responded slowly and inefficiently to the accelerator, so it would “grow” a larger gas tank and waste gas trying to get up to speed or something. This inefficiency “explains” why the driver pushes the gas pedal excessively. There is no need for psychological postulates about the driver.

2. Geoff: “…people who are hyperinsulinemic, as far as I know, usually or always have high fasting glucose. The question is what causes this high fasting glucose, and I don't think that dietary carbohydrates are a good explanation for this.”

Todd: I agree that dietary carbohydrates don’t cause hyperinsulinemia or hyperglycemia. The cause of elevated blood glucose is no mystery: Insulin resistance reduces the number and efficiency GLUT4, allowing glucose levels to rise. The pancreas upregulates insulin secretion to counteract this to some extent, but process is still inefficient. Once IR is in place, however, carbohydrate ingestion maintains obesity by not allowing basal insulin to fall.

3. Geoff: “You still have not explained how the body of an obese, IR individual goes into overdrive in response to overeating if it is insulin driving fat storage in response to dietary carbohydrates rather than the brain in response to elevated leptin levels in the blood. This is the major problem with settling point theories of obesity. They explain what prevents the level from going down, but they don't explain what prevents it from going up.”

Todd: It’s not either/or. It is the combination of IR and carbohydrates that drive obesity. The weak insulin hypothesis holds only that high carbohydrate consumption is a necessary condition; insulin- (and leptin-) resistance are also required to drive obesity.

You claim that leptin resistance, not insulin resistance is the driver (or at least a necessary condition) for obesity. However, experiments by Lustig suggest that hyperinsulinemia causes leptin resistance:

http://bit.ly/r0BpDV

By administering an insulin agonist (octreotide-LAR) to obese adults, he reversed their hyperinsulinemia and secondarily their leptin resistance, leading to dramatic weight loss. This is a pretty strong demonstration of the essential causal role that hyperinsulinemia (which results from IR) plays in obesity.

4. Geoff “ultimately, the hypothalamus decides whether to release fat or not based on what it thinks is going on in the body. Again, I would say that the "weak" form of the insulin hypothesis put forward has much more problems explaining the release from fat tissue, because somehow the body needs to get access to this fat in spite of the elevated insulin inhibiting lipolysis.”

Todd: The hypothalamus’ “decision” about whether to release fat is governed by how much leptin crosses the blood-brain barrier. Hyperinsulinemia impairs detection of leptin, so the body holds onto fat. This is a direct consequence of the weak insulin hypothesis, which holds that both carbohydrates AND insulin resistance are required for obesity. While hyperinsulinemia thus “inhibits” lipolysis and fat oxidation, it certainly doesn’t shut it down. This inhibition becomes progressively inefficient in advanced obesity, while still being sufficient to maintain obesity. – as Strontium’s “balloon” analogy nicely illustrates. However, if you administer ocretotide or another insulin agonist, obesity disappears!

The weak insulin hypothesis is consistent with all the above facts, so I see no reason to abandon it at this point.

@Todd and StrontiumI think the leaky balloon analogy is a bit off – insulin is not the balloon pump. Instead, it is more like the fuel the balloon pump uses to do its job. The more fuel the body supplies to the pump, the more pressure it provides. Now suppose the balloon pump for some reason becomes less efficient at using the fuel. Then the pump needs to be provided with more fuel in order to maintain the same level of pressure. Increased fuel (insulin) only results in a bigger balloon if the increase is sufficiently large enough to overcome the decreased efficiency of the pump.

While it’s theoretically possible for hyperinsulinemia in the obese be high enough to overcome the effects of insulin resistance, there doesn’t seem to be any evidence that this is what is happening, and quite a bit of evidence against it.

It’s possible there are other pathways by which hyperinsulinemia might be a factor in the development of obesity, like leptin resistance or reactive hypoglycemia. But the specific theory Taubes has advocated doesn’t seem to be plausible.

There's often little point arguing about which analogy more closely reflects reality, because the trouble with analogies is they're never exact.

However, the evidence is that insulin resistance is related to the size of the adipocyte. Your analogy decouples the analogue of insulin resistance from the analogue of adipocyte size, so it doesn't seem likely to explain very much.

You could modify your analogy so that the efficiency of the pump is somehow affected by the size of the balloon, but then explore what happens. The only way of reducing the efficiency of the pump is to increase the volume of the balloon and that means the fuel supply must first have increased. The fuel supply doesn't increase instantaneously, so it is unphysical to imagine that you can go from a state in which the balloon is being inflated (the fuel supply increased a bit) to a state in which the balloon is deflating (the pump efficiency decreased ) without going through an intermediate state in which the balloon is neither inflating nor deflating (the reduction in pump efficiency exactly balanced the increased fuel supply). Once you reach that state, that's where you stay, but importantly, the balloon is a bit bigger than it was.

This is the consequence of any dynamic equilibrium or “settling point” explanation. The specifics of how insulin sensitivity varies with adipocyte size do not matter, all that matters is that the former depends on the latter; in that case, more insulin will ALWAYS correspond to a larger adipocyte for the reasons I just gave.

interesting article, by the way if you have leaky fat cells that is bad, this is a indication that the fat cells cell membranes are deficient in cholesterol. this keeps the cells guts intact.

also fat cells can release fat in high insulin simply because the other cells cannot use glucose very well and depend on fat more than anything and hence adrenalin forces fat release in enviroment of high insulin, hence the gitteriness and hard to sleep at night problem when insulin levels are still to high.

also fat cells can become glucose intolerant due to malnutrtion lack of enough calcium, fats, vita d, cholesterol to handle the transport of a highly oxidative substance as gluocose through their cytoplasm to the mitrochondria,

this happens in all cells not just fat cells in fact fat cells are also responsible for cholesterol storage, cholesterol repair, and storage of fat soluable vitamins when these tend to be reduced. hoarding as it were prventing other cells from having calcium vita d etc for themselves to handle glucose. if you are releaseing calcitron (I can't spell worth anyting) your fat cells will proliferate to handle the storage needs of a glucose intolerant person, also your fat cells are responsible for turning glucose into fat and if your cells cannot use gluocse they have to use fat. in other words you get fat due to malfunction of your metabolism.

malnutrtion will ensure this, if your a dieter (hypocaloire diets) or a low fat eater, or heavy process eater your malnorished. personally I did not realize glucose was like gasoline in your system it reacts readily to oxygen. and whoever said our inners were combustion engines especially if you don't change to oil or put oil in there in sufficient quantity in the first place or use poor quality oils.

in fat saturated fats are the most least oxidative substance for fuel. it lasts longer and oh yea forgot your fats are not just used for energy, but for cellular membranes which turnover fats daily as the fat become rancid. 50 percent of cells are composed of fats. cholesterol too which has to be turned over regularly for repair.

source is article the "obesity is the metabolic syndrome a nutrtional deficency" with links to other articles about cholesterol and sat fat and glucose and fructose. check it out.

Does IR have any effect on calories in vs out? i.e. how does it effect weight loss/weight gain? does the person with IR have more of the incoming calories stored as fat (rather than muscle or "other areas where it is needed") than the non-IR person?

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I'm an obesity researcher, neurobiologist, and author. In addition to my research, I enjoy synthesizing and communicating science for a general audience. I have a BS in biochemistry (University of Virginia) and a PhD in neurobiology (University of Washington).
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